www.symbiosisonline.org Symbiosis www.symbiosisonlinepublishing.com Review Article SOJ Immunology Open Access Skeletal and Joint Manifestations of Primary Immunodeficiency Diseases Asal Gharib* and Sudhir Gupta Programs in Primary Immunodeficiency and Aging, Division of Basic and Clinical Immunology, University of California, Irvine, USA Received: May 23, 2016; Accepted: June 16, 2016; Published: June 24, 2016 *Corresponding author: Asal Gharib, Division of Basic and Clinical Immunology, University of California at Irvine, Medical Sci. I, C-240, Irvine,CA 92697, USA, Tel: +949-824-5818; Fax: +949-824-4362; E-mail: agharib@ uci.edu Methods Absract The information offered in this article is based upon PubMed disorders in the innate or adaptive immune systems, or combinations (Medline) and Scopus search engines for the search terms of each of disordersPrimary inImmunodeficiencies both. The underlying (PIDs) disorder occur may due be attributedto inherited to individual disease state and one of the following: arthritis, skeletal, musculoskeletal, osteoporosis, osteopenia, or osteomyelitis. The immune components. There are 200 different PIDs and more than inclusion criteria included Humans and English as the language. 270decreased genes levels,have been decreased described function, that are or associated complete withnonfiction or cause of Results categories using the International Union of Immunological Societies PIDs. These PIDs have recently been re-classified into nine different Skeletal and joint abnormalities in nine different categories highlights the different manifestations, including infectious as well are shown in the Tables 1-9. Skeletal abnormalities are discussed as(IUIS) noninfectious classification etiologies of Primary that may Immunodeficiencies. occur in the skeletal This system review of in detail. Discussion patientsKeywords: with primary Immunodeficiencies. Primary immunodeficiency; Arthritis; Osteopenia; display a number of musculoskeletal changes. In patients Osteomyelitis; Bone findings; Skeletal findings; Bone anomalies; Joint Patients with certain types of primary immunodeficiencies findings Introduction pyogenic bacteria or mycoplasmal arthritis is the most common osteoarticularwith primary manifestation.immunodeficiencies, In certain septic PIDs, arthritis chronic, due non- to infectious arthritis resembling rheumatoid arthritis may occur. In this paper we have extensively reviewed musculoskeletal and Primary Immune deficiencies (PIDs) are inherited disorders osteoarticular changes in PIDs and presented them under most that qualitatively or quantitatively affect components of the innate and adaptive immune systems. The pulmonary [1], dermatological [2], gastrointestinal [3], rheumatological recentIn IUISSCID, primary a number immunodeficiency of patients developing classification. osteomyelitis [4], autoimmune [5], and hematological/oncological [6,7] following BCG vaccination have been reported [11]. A T-B+NK+ SCID patient developed arthritis and manifestations of PIDs have been reviewed. However, skeletal Mycobacteria marinum osteomyelitis [12]. Reticular dysgenesis is associated with manifestations of PIDs have not been reviewed. There are 200 bone anomalies of square shaped scapular tips and cupped different PIDs and more than 270 genes have been described that costochondral junctions [13]. Characteristic skeletal changes are associated with or cause PIDs. Registry data has been used in of anterior rib junction, metaphyseal changes, and scapular epidemiological studies to gauge PID prevalence: 5.38/100,000 squaring have been reported in SCID due to adenosine deaminase in France, 5.6/100,000 in Australia, USA 86.3/100,000 inhabitants [8]. Bousfiha and colleagues [9] calculated the ]. number of PID cases based on the prevalence estimates which deficiency [14,15]. Chronic adenoviral arthritis and microcephaly ranges from 390,546 using the Australian model, 6 million using haveIn been Wiskott- reported Aldrich in Cernunnos syndrome, deficiency 29% of patients [16 have aseptic arthritis [17-20]. Ataxia Telangiectasia has been associated the USA model while PID registries and Jeffrey Modell Centers with rickets where all three members of a family had rickets list 27,243-60,000 cases. These PIDs have recently been re- [21]. Ataxia Telangiectasia-like syndrome has been associated classified into nine different categories. PID treatment ranges . ]. Nijmegen-Breakage from immunoglobulin replacement therapy to hematopoietic syndrome (a rare DNA repair disorder characterized by stem cell transplant [10] We present a comprehensive review of with microcephaly in 40% of patients [22 skeletal and joint manifestations in PIDs according to the most recent classifications. microcephaly, immunodeficiency, and predisposition to Symbiosis Group *Corresponding author email: agharib@ uci.edu Skeletal and Joint Manifestations of Primary Immunodeficiency Diseases Copyright: © 2016 Gharib et al. Table 1: Diseases Severe Combined Immunodeficiencies. Bone/Joint Findings Reference # [11] T-B+ SCID Osteomyelitis T-B- SCID a. RAG2 deficiency Osteomyelitis [159] - scapular tip squaring [13] Bone -anomalies: costochondral junction cupping b. Reticular Dysgenesis AK2 deficiency Septic Arthritis [16] c. Cernunnos Deficiency - Microcephaly [160,161] Bone -anomalies: Severe growth failure d. DNA Ligase IV deficiency - Bone anomalies: e. Adenosine Deaminase Deficiency [162][14-15] Chondro-osseus dysplasia f. MHC Class I deficiency Osteomyelitis - [163] Bone -Anomalies: low implanted thumb g. MHC Class II deficiency Dolichocephaly Table 2: Diseases Bone/Joint Findings Reference # Well Defined Syndrome with Immunodeficiencies. Congenital Thrombocytopenia Aseptic Arthritis Arthralgia a. Wiskott-Aldrich Syndrome [17-20] DNA Repair Defects Aseptic Arthritis [21] Rickets a. Ataxia-Telangiectasia Microcephaly [22] b. Ataxia- Telangiectasia Like Disease - hip dysplasia c. Nijmegen Breakage Syndrome -Bone ribanomalies: dysplasia [23-26] - sacral genesis - clinodactyly - polydactyly - microcephaly - scoliosis - absent thumbs - Juvenile Idiopathic Arthritis - dolichocephaly d. Bloom Syndrome Bone -anomalies: short stature [27] And Facial Anomalies (ICF) - syndactyly e. Immunodeficiency with centromeric Instability Bone -anomalies: Juvenile Idiopathic Arthritis [28-30] Short Stature Thymic Defects with additional congenital anomalies f. MCM4 deficiency [164] [31,32] Juvenile Idiopathic Arthritis a. DiGeorge Syndrome Bone Anomalies Immune-Osseus Dysplasias: a. Cartilage Hair Hypoplasia Aseptic Arthritis - Metaphyseal chondrodysplasia [33,34] Bone -anomalies: genu varum - - brachydactyly - macrocephalymetaphyseal flaring - lordosis Citation: Page 2 of 13 Gharib A, Gupta S (2016) Skeletal and Joint Manifestations of Primary Immunodeficiency Diseases. SOJ Immunol 4(1): 1-13. DOI: http://dx.doi.org/10.15226/2372-0948/4/1/00145 Skeletal and Joint Manifestations of Primary Immunodeficiency Diseases Copyright: © 2016 Gharib et al. b. Schimke Syndrome Aseptic Arthritis - epiphyseal dysplasia [35,36] Bone -anomalies: metaphyseal dysplasia - platyspondyly - vertebral anomalies - lordosis Hyper IgE Syndrome - scoliosis a. AD-HIES (Job’s Syndrome) Bone -anomalies: recurrent fractures [37,39,40-46] - Septic Arthritis - Scoliosis Osteomyelitis b. DOCK8 deficiency FracturesLupus Arthritis [47,48] Dyskeratosis Congenital (DKC) - phalangeal absorption a. XL-DKC Bone -anomalies: fractures [49,158] - avascular necrosis Microcephaly b. AR-DKC due to RTEL deficiency Scoliosis [50] c. AD-DKC due to TERT deficiency Bone anomaly [51] Osteoporosis - epiphyseal osteosclerosis Comel - Netherton Syndrome Bone -anomalies: rickets [52,53] Juvenile Idiopathic Arthritis ORA-I Deficiency Bone anomaly: club foot [54] Microcephaly STAT 5b deficiency [87] Hepatic Veno-Occlusive Disease with immunodeficiency [55] (VODI) TableFILS Syndrome 3: Bone Anomaly: macrocephaly [56] Diseases Bone/Joint Findings Reference # Predominantly Antibody Deficiency. Aseptic Arthritis Septic Arthritis BTK Deficiency [57-61] Aseptic ArthritisOsteomyelitis Septic Osteomyelitis Aseptic Arthritis [63] µ heavy chain deficiency [62,165] Aseptic Arthritis ʎ5 deficiency Septic Arthritis Thymoma with immunodeficiency (Good Syndrome) Septic Arthritis [64,65] Rheumatoid Arthritis Common Variable Immunodeficiency [66-70,166] Rheumatoid Arthritis Septic Osteomyelitis ICOS deficiency [71,72] Warts, Hypogammaglobulinemia, infection, TWEAK Deficiency Osteomyelitis [73] Osteomyelitis [74] Myelokathexis Syndrome (WHIM) Aseptic Arthritis CD40L deficiency Osteomyelitis, Unspecified [75] Septic Arthritis AID Deficiency [76,77] Isolated IgG Subclass deficiency Rheumatoid Arthritis [78] Osteomyelitis IgA with IgG subclass deficiency [79] PRKC δ Bone Anomalies: [80] Juvenile-microcephaly Idiopathic Arthritis Rheumatoid-polysyndactyly Arthritis Selective IgA Deficiency [81-84] Osteomyelitis Citation: Page 3 of 13 Gharib A, Gupta S (2016) Skeletal and Joint Manifestations of Primary Immunodeficiency Diseases. SOJ Immunol 4(1): 1-13. DOI: http://dx.doi.org/10.15226/2372-0948/4/1/00145 Skeletal and Joint Manifestations of Primary Immunodeficiency Diseases Copyright: © 2016 Gharib et al. Table 4: Diseases Diseases of Immune Dysregulation. Bone/Joint Findings Reference # Juvenile Idiopathic Arthritis UNC13D/MUNC 13-4 Deficiency Arthritis [85] syndrome) IPEX (Immune dysregulation, polyendocrinopathy, enteropathy, X-linked Short Stature [86] dysplasia) Juvenile Rheumatoid Arthritis APCED (Autoimmune polyendocrinopathy candidiasis